Patients whose advanced non-small cell lung cancer (NSCLC) tested positive for the ROS1 fusion protein receptor tyrosine kinase (encoded by the ROS1 oncogene) had high response rates with low toxicities when treated with a next-generation ROS1 tyrosine kinase inhibitor (TKI), repotrectinib, in the Phase I/II Trident-1 study. Findings were reported at the 34th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain (Abstract 2LBA).
The trial had so far included more than 400 patients with ROS1-positive NSCLC (1% or 2% of all lung cancer cases) who were treated at one of 150 hospitals around the world. Some had never been treated with a ROS1 TKI, some had already been treated with one ROS1 TKI, some had been treated with a ROS1 TKI and platinum-based chemotherapy, and some had been treated with two different ROS TKIs. As of June 20, 2022, the primary efficacy population had included 71 TKI-naive patients and 56 TKI-pretreated patients with no prior chemotherapy.
"In TKI-naive patients, repotrectinib showed a 78 percent objective response rate (tumor reduction of at least 30%) and the 12 months duration of response was 86 percent," said first author Byoung Chul Cho, MD, PhD, Thoracic Medical Oncologist with the Yonsei Cancer Center at Yonsei University College of Medicine in Seoul, South Korea, talking with Oncology Times after his late-breaking session at the symposium. In the patients with no prior chemotherapy who had been treated with a previous-generation ROS1 TKI, Cho said they also found a good response rate. "Repotrectinib showed a 37 percent objective response rate with a 6-month duration of response [of] 79 percent."
A significant issue with ROS1 TKI treatment had been that patients usually developed the so-called G2032R resistance mutation that rendered further TKI therapy ineffective. "The G2032R resistance mutation is the most common resistance mechanism," Cho noted. "Repotrectinib showed objective response rate of 58 percent in this population."
Another putative advantage for the investigational agent in Trident-1 had been that it also inhibited mutated tropomyosin receptor kinase (TRK) receptor, a molecular feature often found in association with ROS1.
"So, in the Trident-1 trial, we also evaluated the activity and safety of repotrectinib in NTRK fusion-positive solid tumors in both TKI-naive and TKI-pretreated populations," Cho said. A Phase I study by Besse and colleagues from Villejuif, France-working on Trident-1 in collaboration with Cho and others-had already found that repotrectinib demonstrated efficacy in TKI-naive and TKI-pretreated patients and was generally well-tolerated (Mol Cancer Ther 2021; https://doi.org/10.1158/1535-7163.TARG-21-P02-01).
When Cho was asked about the impact of the new TKI on cranial metastases, he said the drug had been effective. "CNS metastasis is one of the [most common] sites of metastasis after progression on a ROS1 TKI. In this study, we [observed] a very high intracranial activity of repotrectinib in both TKI-naive and TKI pre-treated populations."
Nearly 90 percent of the small number of patients with measurable tumors in the brain not previously treated with a ROS1 TKI had intracranial objective responses (iORR). Just less than half of those already treated with one prior ROS1-and half of those treated with one prior ROS1 TKI and chemotherapy-had iORR. But none of the patients pre-treated with both chemotherapy and a TKI had responded.
Cho said that repotrectinib had been generally well-tolerated. "The most common side effects were low-grade: Grade 1 or 2. The most common was low-grade dizziness. It occurred in about 60 percent of patients," he said. But despite this relatively high incidence of dizziness, the incidence of treatment discontinuation had been low-less than 10 percent.
"With around 16 months median follow-up, the median duration of response to repotrectinib treatment in TKI-naive patients has not yet been met. This is very meaningful and a clear measure to utilize repotrectinib in the TKI-naive setting," Cho explained. "We also demonstrated a high response rate in TKI-pre-treated ROS1-positive lung cancer...and the activity of repotrectinib in G2032R-mutant ROS1-positive lung cancer."
Cho regarded the data as the strongest yet seen with a TKI in this setting. "In our study, we demonstrated the potential role and value of repotrectinib in both TKI-naive and TKI-pretreated, ROS1-positive, advanced-stage NSCLC."
For many patients with the ROS1 marker, he predicted an important role for repotrectinib in picking up the baton to take over from previous generation TKI therapy.
"Because the current standard of care at the time of diagnosis of advanced stage ROS1-positive lung cancer is a ROS1 TKI such as crizotinib or entrectinib, after 15 or 20 months of progression-free survival, the majority of patients experience disease progression due to acquired resistance," Cho said. "So, in the second-line setting, we [currently] only have cytotoxic chemotherapy. These data support the use of repotrectinib in the setting of resistance to prior ROS1 TKI in the first-line setting. Our data suggest that repotrectinib could represent a potential new treatment option for patients with ROS1-positive NSCLC in both TKI-naive and TKI pre-treated populations."
Peter Goodwin is a contributing writer.